This competing renewal application describes an interrelated series of clinical and preclinical studies of an alteration in platelet membrane fluidity associated with primary dementia in the elderly. Increased platelet membrane fluidity (PMF), as measured by a decrease in the fluorescence anisotropy of 1,6-diphenyl-1,3,5-hexatriene (DPH) in labeled membranes, identifies a subgroup of patients with Alzheimer's disease (AD) who have distinct clinical features. This phenotype appears to be a stable, familial trait that is vertically transmitted in families of patients with Alzheimer's disease. Segregation analysis of data from these families indicates that increased PMF results from the inheritance of a single major locus that controls at least 80% of the variance in this membrane phenotype. At the cellular level, evidence from ultrastructural and biochemical studies suggests that increased PMF results from an accumulation of abnormal internal membranes resembling smooth endoplasmic reticulum that may be functionally abnormal. We hypothesize that this inherited abnormality is expressed in the brain and contributes to the formation of senile plaques and neurofibrillary tangles, the histologic hallmarks of AD. During the requested award period, we propose to prospectively evaluate increased PMF as a risk factor for AD, to further define the cellular and molecular basis for increased PMF, and to use this information to direct hypothesis-driven studies of post-mortem brain tissue aimed at elucidating the pathophysiology of AD.